Analysis of gliomas DNA methylation: Assessment of pre-analytical variables.

Precision oncology is driven by molecular biomarkers. For glioblastoma multiforme (GBM), the most common malignant adult primary brain tumor, O6-methylguanine-DNA methyltransferase ( MGMT ) gene DNA promoter methylation is an important prognostic and treatment clinical biomarker. Time consuming pre-analytical steps such as biospecimen storage before fixing, sampling, and processing are major sources of errors and batch effects, that are further confounded by intra-tumor heterogeneity of MGMT promoter methylation. To assess the effect of pre-analytical variables on GBM DNA methylation, tissue storage/sampling (CryoGrid), sample preparation multi-sonicator (PIXUL) and 5-methylcytosine (5mC) DNA immunoprecipitation (Matrix MeDIP-qPCR/seq) platforms were used. MGMT promoter CpG methylation was examined in 173 surgical samples from 90 individuals, 50 of these were used for intra-tumor heterogeneity studies. MGMT promoter methylation levels in paired frozen and formalin fixed paraffin embedded (FFPE) samples were very close, confirming suitability of FFPE for MGMT promoter methylation analysis in clinical settings. Matrix MeDIP-qPCR yielded similar results to methylation specific PCR (MS-PCR). Warm ex-vivo ischemia (37°C up to 4hrs) and 3 cycles of repeated sample thawing and freezing did not alter 5mC levels at MGMT promoter, exon and upstream enhancer regions, demonstrating the resistance of DNA methylation to the most common variations in sample processing conditions that might be encountered in research and clinical settings. 20-30% of specimens exhibited intratumor heterogeneity in the MGMT DNA promoter methylation. Collectively these data demonstrate that variations in sample fixation, ischemia duration and temperature, and DNA methylation assay technique do not have significant impact on assessment of MGMT promoter methylation status. However, intratumor methylation heterogeneity underscores the need for histologic verification and value of multiple biopsies at different GBM geographic tumor sites in assessment of MGMT promoter methylation. Matrix-MeDIP-seq analysis revealed that MGMT promoter methylation status clustered with other differentially methylated genomic loci (e.g. HOXA and lncRNAs), that are likewise resilient to variation in above post-resection pre-analytical conditions. These MGMT -associated global DNA methylation patterns offer new opportunities to validate more granular data-based epigenetic GBM clinical biomarkers where the CryoGrid-PIXUL-Matrix toolbox could prove to be useful.

DOTATATE PET/MR Imaging Differentiates Secondary-Progressive from de Novo World Health Organization Grade 3 Meningiomas.

BACKGROUND AND PURPOSE: WHO grade 3 meningiomas are rare and poorly understood and have a higher propensity for recurrence, metastasis, and worsened clinical outcomes compared with lower-grade meningiomas. The purpose of our study was to prospectively evaluate the molecular profile, PET characteristics, and outcomes of patients with World Health Organization grade 3 meningiomas who were imaged with gallium 68 (68Ga) DOTATATE PET/MR imaging. MATERIALS AND METHODS: Patients with World Health Organization grade 3 meningiomas enrolled in our prospective observational cohort evaluating the utility of (68Ga) DOTATATE PET/MR imaging in somatostatin receptor positive brain tumors were included. We stratified patients by de novo-versus-secondary-progressive status and evaluated the differences in the PET standard uptake value, molecular profiles, and clinical outcomes. RESULTS: Patients met the inclusion criteria (secondary-progressive: 7/14; de novo: 7/14). The secondary-progressive cohort had a significantly higher per-patient number of surgeries (4.1 versus 1.6; P = .011) and trended toward a higher number of radiation therapy courses (2.4 versus 1.6; P = .23) and cumulative radiation therapy doses (106Gy versus 68.3Gy; P = .31). The secondary-progressive cohort had a significantly lower progression-free survival compared with the de novo cohort (4.8 versus 37.7 months; P = .004). Secondary-progressive tumors had distinct molecular pathology profiles with higher numbers of mutations (3.5 versus 1.2; P = .024). Secondary-progressive tumors demonstrated higher PET standard uptake values (17.1 versus 12.4; P = .0021). CONCLUSIONS: Our study confirms prior work illustrating distinct clinical outcomes in secondary-progressive and de novo World Health Organization grade 3 meningiomas. Furthermore, our findings support (68Ga) DOTATATE PET/MR imaging as a useful management strategy in World Health Organization grade 3 meningiomas and provide insight into meningioma biology, as well as clinical management implications.

[Ga68] DOTATATE PET/MRI-Guided Radiosurgical Treatment Planning and Response Assessment in Meningiomas.

BACKGROUND: Our purpose was to determine the utility of [68Ga]-DOTATATE PET/MRI in meningioma response assessment following radiosurgery. METHODS: Patients with meningioma prospectively underwent postoperative DOTATATE PET/MRI. Co-registered PET and gadolinium-enhanced T1-weighted MRI were employed for radiosurgery planning. Follow-up DOTATATE PET/MRI was performed at 6-12 months post radiosurgery. Maximum absolute standardized uptake value (SUV) and SUV ratio (SUVRSSS) referencing superior sagittal sinus (SSS) blood pool were obtained. Size change was determined by Response Assessment in Neuro-Oncology (RANO) criteria. Association of SUVRSSS change magnitude and PFS was evaluated using Cox regression. RESULTS: 27 patients with 64 tumors (26% WHO-1, 41% WHO-2, 26% WHO-3, 7% WHO-unknown) were prospectively followed post stereotactic radiosurgery (SRS) or stereotactic body radiotherapy (SBRT) (mean dose: 30 Gy, modal dose 35 Gy, mean of 5 fractions). Post-irradiation SUV and SUVRSSS decreased by 37.4% and 44.4%, respectively (p < 0.0001). Size product decreased by 8.9%, thus failing to reach the 25% significance threshold as determined by RANO guidelines. Mean follow-up time was 26 months (range: 6-44). Overall mean PFS was 83% and 100%/100%/54% in WHO-1/-2/-3 subcohorts, respectively, at 34 months. At maximum follow-up (42-44 months), PFS was 100%/83%/54% in WHO-1/-2/-3 subcohorts, respectively. Cox regression analyses revealed a hazard ratio of 0.48 for 10-unit reduction in SUVRSSS in the SRS cohort. CONCLUSIONS: DOTATATE PET SUV and SUVRSSS demonstrated marked, significant decrease post radiosurgery. Lesion size decrease was statistically significant, however it was not clinically significant by RANO criteria. DOTATATE PET/MR thus represents a promising imaging biomarker for response assessment in meningiomas treated with radiosurgery.

Autologous cell immunotherapy (IGV-001) with IGF-1R antisense oligonucleotide in newly diagnosed glioblastoma patients.

Standard-of-care first-line therapy for patients with newly diagnosed glioblastoma (ndGBM) is maximal safe surgical resection, then concurrent radiotherapy and temozolomide, followed by maintenance temozolomide. IGV-001, the first product of the Goldspire™ platform, is a first-in-class autologous immunotherapeutic product that combines personalized whole tumor-derived cells with an antisense oligonucleotide (IMV-001) in implantable biodiffusion chambers, with the intent to induce a tumor-specific immune response in patients with ndGBM. Here, we describe the design and rationale of a randomized, double-blind, phase IIb trial evaluating IGV-001 compared with placebo, both followed by standard-of-care treatment in patients with ndGBM. The primary end point is progression-free survival, and key secondary end points include overall survival and safety.

Glioblastoma (GBM) is a fast-growing brain tumor that happens in about half of all gliomas. Surgery is the first treatment for patients with newly diagnosed GBM, followed by the usual radiation and chemotherapy pills named temozolomide. Temozolomide pills are then given as a long-term treatment. The outcome for the patient with newly diagnosed GBM remains poor. IGV-001 is specially made for each patient. The tumor cells are removed during surgery and mixed in the laboratory with a small DNA, IMV-001. This mix is the IGV-001 therapy that is designed to give antitumor immunity against GBM. IGV-001 is put into small biodiffusion chambers that are irradiated to stop the growth of any tumor cells in the chambers. In the phase IIb study, patients with newly diagnosed GBM are chosen and assigned to either the IGV-001 or the placebo group. A placebo does not contain any active ingredients. The small biodiffusion chambers containing either IGV-001 or placebo are surgically placed into the belly for 48 to 52 h and then removed. Patients then receive the usual radiation and chemotherapy treatment. Patients must be adults aged between 18 and 70 years. Patients also should be able to care for themselves overall, but may be unable to work or have lower ability to function. Patients with tumors on both sides of the brain are not eligible. The main point of this study is to see if IGV-001 helps patients live longer without making the illness worse compared with placebo. Clinical Trial Registration: NCT04485949 (ClinicalTrials.gov).

Olfactory groove meningiomas: supraorbital keyhole versus orbitofrontal, frontotemporal, or bifrontal approaches.

OBJECTIVE: Olfactory groove meningiomas (OGMs) often require surgical removal. The introduction of recent keyhole approaches raises the question of whether these tumors may be better treated through a smaller cranial opening. One such approach, the supraorbital keyhole craniotomy, has never been compared with more traditional open transcranial approaches with regard to outcome. In this study, the authors compared clinical, radiographic, and functional quality of life (QOL) outcomes between the keyhole supraorbital approach (SOA) and traditional transcranial approach (TTA) for OGMs. They sought to examine the potential advantages and disadvantages of open/TTA versus keyhole SOA for the resection of OGMs in a relatively case-matched series of patients. METHODS: A retrospective, single-institution review of 57 patients undergoing a keyhole SOA or larger traditional transcranial (frontotemporal, pterional, or bifrontal) craniotomy for newly diagnosed OGMs between 2005 and 2023 was performed. Extent of resection, olfaction, length of stay (LOS), radiographic volumetric assessment of postoperative vasogenic and cytotoxic edema, and QOL (using the Anterior Skull Base Questionnaire) were assessed. RESULTS: Thirty-two SOA and 25 TTA patients were included. The mean EOR was not significantly different by approach (TTA: 99.1% vs SOA: 98.4%, p = 0.91). Olfaction was preserved or improved at similar rates (TTA: 47% vs SOA: 43%, p = 0.99). The mean LOS was significantly shorter for SOA patients (4.1 ± 2.8 days) than for TTA patients (9.4 ± 11.2 days) (p = 0.002). The authors found an association between an increase in postoperative FLAIR cerebral edema and TTA (p = 0.031). QOL as assessed by the ASQB at last follow-up did not differ significantly between groups (p = 0.74). CONCLUSIONS: The keyhole SOA was associated with a statistically significant decrease in LOS and less postoperative edema relative to traditional open approaches.

Combined surgical repair and venous sinus stenting for patients with skull base encephaloceles secondary to dural venous sinus stenosis.

BACKGROUND: Chronically elevated intracranial pressure (ICP) seen in idiopathic intracranial hypertension (IIH) can cause the development of skull base encephaloceles and cerebrospinal fluid (CSF) leaks. Surgical repair and ventriculoperitoneal shunt (VPS) placement are mainstays of treatment. Venous sinus stenting (VSS) is a newly accepted treatment modality. The goal of this study was thus to determine if VSS can be used to treat symptoms and prevent recurrence after surgical encephalocele repair. METHODS: Retrospective chart review of patients that had surgical repair of encephaloceles followed by VSS for symptomatic stenosis with elevated pressure gradient. RESULTS: A total of 13 patients underwent a combined encephalocele repair and VSS. Seventy-two percent were female; 46% had headaches, 69% pulsatile tinnitus, and 92% CSF rhinorrhea or otorrhea. One had seizures. Mean lumbar opening pressure was 23.3 ± 2.6 cm H2O; the average sagittal-to-jugular pressure gradient was 12.7 ± 1.8 cmH2O and was elevated in all patients. Four patients had middle fossa craniotomy for repair of tegmen defect (one bilateral); one had a retrosigmoid craniotomy for repair of a sigmoid plate defect. Eight had an endoscopic endonasal repair for sphenoid or cribriform plate encephalocele. There were no VSS procedural complications or complications associated with dual antiplatelet therapy. One patient had meningitis after endoscopic repair that was treated with antibiotics. One patient had recurrence of both CSF leak and venous stenosis adjacent to the stent requiring repeat repair and VSS. There was no further recurrence. CONCLUSION: In patients with dural sinus stenosis and encephaloceles requiring repair, VSS can be performed safely within weeks of surgery for relief of symptoms, resolution of underlying pathology, and prevention of CSF leak recurrence.

Oncolytic DNX-2401 virotherapy plus pembrolizumab in recurrent glioblastoma: a phase 1/2 trial.

Immune-mediated anti-tumoral responses, elicited by oncolytic viruses and augmented with checkpoint inhibition, may be an effective treatment approach for glioblastoma. Here in this multicenter phase 1/2 study we evaluated the combination of intratumoral delivery of oncolytic virus DNX-2401 followed by intravenous anti-PD-1 antibody pembrolizumab in recurrent glioblastoma, first in a dose-escalation and then in a dose-expansion phase, in 49 patients. The primary endpoints were overall safety and objective response rate. The primary safety endpoint was met, whereas the primary efficacy endpoint was not met. There were no dose-limiting toxicities, and full dose combined treatment was well tolerated. The objective response rate was 10.4% (90% confidence interval (CI) 4.2-20.7%), which was not statistically greater than the prespecified control rate of 5%. The secondary endpoint of overall survival at 12 months was 52.7% (95% CI 40.1-69.2%), which was statistically greater than the prespecified control rate of 20%. Median overall survival was 12.5 months (10.7-13.5 months). Objective responses led to longer survival (hazard ratio 0.20, 95% CI 0.05-0.87). A total of 56.2% (95% CI 41.1-70.5%) of patients had a clinical benefit defined as stable disease or better. Three patients completed treatment with durable responses and remain alive at 45, 48 and 60 months. Exploratory mutational, gene-expression and immunophenotypic analyses revealed that the balance between immune cell infiltration and expression of checkpoint inhibitors may potentially inform on response to treatment and mechanisms of resistance. Overall, the combination of intratumoral DNX-2401 followed by pembrolizumab was safe with notable survival benefit in select patients (ClinicalTrials.gov registration: NCT02798406).

Safety and efficacy of Cesium-131 brachytherapy for brain tumors.

BACKGROUND: The introduction of Cesium-131 (Cs-131) as a radiation source has led to a resurgence of brachytherapy for central nervous system (CNS) tumors. The aim of this study was to evaluate the safety and efficacy of the largest cohort of Cs-131 patients to-date. METHODS: A retrospective review of all CNS tumors treated with resection and adjuvant Cs-131 brachytherapy at New York-Presbyterian/Weill Cornell from 2010 to 2021 was performed. Overall survival (OS) and local control (LC) were assessed with Kaplan-Meier methodology. Univariable analysis was conducted to identify patient factors associated with local recurrence or radiation necrosis. RESULTS: Adjuvant Cs-131 brachytherapy following resection was performed in 119 patients with a median follow-up time of 11.8 (IQR 4.7-23.6) months and a mean of 22.3 +/-30.3 months. 1-year survival rates were 53.3% (95%CI 41.9-64.6%) for brain metastases (BrM), 45.9% (95%CI 24.8-67.0%) for gliomas, and 73.3% (95%CI 50.9-95.7%) for meningiomas. 1-year local control rates were 84.7% for BrM, 34.1% for gliomas, and 83.3% for meningiomas (p < 0.001). For BrM, local control was superior in NSCLC relative to other BrM pathologies (90.8% versus 76.5%, p = 0.039). Radiographic radiation necrosis (RN) was identified in 10 (8.4%) cases and demonstrated an association with smaller median tumor size (2.4 [IQR 1.8-2.7 cm] versus 3.1 [IQR 2.4-3.8 cm], p = 0.034). Wound complications occurred in 14 (11.8%) patients. CONCLUSIONS: Cs-131 brachytherapy demonstrated a favorable safety and efficacy profile characterized by high rates of local control for all treated pathologies. The concept of brachytherapy has seen a resurgence given the excellent results when Cs-131 is used as a source.

Concurrent immunotherapy and re-irradiation utilizing stereotactic body radiotherapy for recurrent high-grade gliomas.

BACKGROUND: Clinical trials evaluating immune checkpoint inhibition (ICI) in recurrent high-grade gliomas (rHGG) report 7%-20% 6-month progression-free survival (PFS), while re-irradiation demonstrates 28%-39% 6-month PFS. AIMS: We evaluate outcomes of patients treated with ICI and concurrent re-irradiation utilizing stereotactic body radiotherapy/fractionated stereotactic radiosurgery (SBRT) compared to ICI monotherapy. METHODS AND RESULTS: Patients ≥18-years-old with rHGG (WHO grade III and IV) receiving ICI + SBRT or ICI monotherapy between January 1, 2016 and January 1, 2019 were included. Adverse events, 6-month PFS and overall survival (OS) were assessed. Log-rank tests were used to evaluate PFS and OS. Histogram analyses of apparent diffusion coefficient maps and dynamic contrast-enhanced magnetic resonance perfusion metrics were performed. Twenty-one patients with rHGG (ICI + SBRT: 16; ICI: 5) were included. The ICI + SBRT and ICI groups received a mean 7.25 and 6.2 ICI cycles, respectively. There were five grade 1, one grade 2 and no grade 3-5 AEs in the ICI + SBRT group, and four grade 1 and no grade 2-5 AEs in the ICI group. Median PFS was 2.85 and 1 month for the ICI + SBRT and ICI groups; median OS was 7 and 6 months among ICI + SBRT and ICI groups, respectively. There were significant differences in pre and posttreatment tumor volume in the cohort (12.35 vs. 20.51; p = .03), but not between treatment groups. CONCLUSIONS: In this heavily pretreated cohort, ICI with re-irradiation utilizing SBRT was well tolerated. Prospective studies are warranted to evaluate potential therapeutic benefits to re-irradiation with ICI + SBRT in rHGG.

Posterior hypothalamic involvement on pre-operative MRI predicts hypothalamic obesity in craniopharyngiomas.

PURPOSE: Hypothalamic obesity (HO) is a complication associated with craniopharyngioma (CP). Attempts have been made to perioperatively predict the development of this complication, which can be severe and difficult to treat. METHODS: Patients who underwent first transsphenoidal surgical resection in a single center between February 2005 and March 2019 were screened; those who have had prior surgery or radiation, were aged below 18 years, or did not have follow up body mass index (BMI) after surgery were excluded. Primary end point was BMI within 2 years post-surgery. Hypothalamic involvement (HI) was graded based on preoperative and postoperative imaging with regards to anterior, posterior, left and right involvement. Data on baseline demographics, pre-operative and post-operative MRI, and endocrine function were collected. RESULTS: 45 patients met the inclusion and exclusion criteria. Most patients in our cohort underwent gross total resection (n = 35 patients). 13 patients were from no HI or anterior HI only group and 22 patients were classified as both anterior (ant) and posterior (post) HI group. There was no significant difference between the two groups in the gross total, subtotal or near total resection. Pre-operative BMI and post-operative BMI were significantly higher in patients who had ant and post HI on pre-operative MRI (p < 0.05 and p < 0.01, respectively). Similarly, post-operative BMI at 13-24 months was also significantly higher in the ant and post HI group on post-op MRI (p < 0.01). There was no significant difference between the two groups in terms of baseline adrenal insufficiency, thyroid insufficiency, gonadal insufficiency, IGF-1 levels, hyperprolactinemia, and diabetes insipidus. Diabetes insipidus was more common following surgery among those who had anterior and posterior involvement on pre-operative MRI (p < 0.05). CONCLUSIONS: HO appears to be predetermined by tumor involvement in the posterior hypothalamus observed on pre-operative MRI. Posterior HI on pre-operative MRI was also associated with the development of diabetes insipidus after surgery.

A multidisciplinary management algorithm for brain metastases.

The incidence of brain metastases continues to present a management issue despite the advent of improved systemic control and overall survival. While the management of oligometastatic disease (ie, 1-4 brain metastases) with surgery and radiation has become fairly straightforward in the era of radiosurgery, the management of patients with multiple metastatic brain lesions can be challenging. Here we review the available evidence and provide a multidisciplinary management algorithm for brain metastases that incorporates the latest advances in surgery, radiation therapy, and systemic therapy while taking into account the latest in precision medicine-guided therapies. In particular, we argue that whole-brain radiation therapy can likely be omitted in most patients as up-front therapy.

Evaluating diagnostic accuracy and determining optimal diagnostic thresholds of different approaches to [68Ga]-DOTATATE PET/MRI analysis in patients with meningioma.

Multiple approaches with [68Ga]-DOTATATE, a somatostatin analog PET radiotracer, have demonstrated clinical utility in evaluation of meningioma but have not been compared directly. Our purpose was to compare diagnostic performance of different approaches to quantitative brain [68Ga]-DOTATATE PET/MRI analysis in patients with suspected meningioma recurrence and to establish the optimal diagnostic threshold for each method. Patients with suspected meningioma were imaged prospectively with [68Ga]-DOTATATE brain PET/MRI. Lesions were classified as meningiomas and post-treatment change (PTC), using follow-up pathology and MRI as reference standard. Lesions were reclassified using the following methods: absolute maximum SUV threshold (SUV), SUV ratio (SUVR) to superior sagittal sinus (SSS) (SUVRsss), SUVR to the pituitary gland (SUVRpit), and SUVR to the normal brain parenchyma (SUVRnorm). Diagnostic performance of the four methods was compared using contingency tables and McNemar's test. Previously published pre-determined thresholds were assessed where applicable. The optimal thresholds for each method were identified using Youden's J statistics. 166 meningiomas and 41 PTC lesions were identified across 62 patients. SUV, SUVRsss, SUVRpit, and SUVRnorm of meningioma were significantly higher than those of PTC (P < 0.0001). The optimal thresholds for SUV, SUVRsss, SUVRpit, and SUVRnorm were 4.7, 3.2, 0.3, and 62.6, respectively. At the optimal thresholds, SUV had the highest specificity (97.6%) and SUVRsss had the highest sensitivity (86.1%). An ROC analysis of SUV, SUVRsss, SUVRpit, and SUVRnorm revealed AUC of 0.932, 0.910, 0.915, and 0.800, respectively (P < 0.0001). Developing a diagnostic threshold is key to wider clinical translation of [68Ga]-DOTATATE PET/MRI in meningioma evaluation. We found that the SUVRsss method may have the most robust combination of sensitivity and specificity in the diagnosis of meningioma in the post-treatment setting, with the optimal threshold of 3.2. Future studies validating our findings in different patient populations are needed to continue optimizing the diagnostic performance of [68Ga]-DOTATATE PET/MRI in meningioma patients.Trial registration: ClinicalTrials.gov Identifier: NCT04081701. Registered 9 September 2019. https://clinicaltrials.gov/ct2/show/NCT04081701 .

Dynamic 68Ga-DOTATATE PET/MRI in the Diagnosis and Management of Intracranial Meningiomas.

Purpose To evaluate dynamic gallium 68 (68Ga) tetraazacyclododecane tetraacetic acid octreotate (DOTATATE) brain PET/MRI as an adjunct modality in meningioma, enabling multiparametric standardized uptake value (SUV) and Patlak net binding rate constant (Ki) imaging, and to optimize static acquisition period. Materials and Methods In this prospective study (ClinicalTrials.gov no. NCT04081701, DOMINO-START), 68Ga-DOTATATE PET/MRI-derived time-activity curves (TACs) were measured in 84 volumes of interest in 19 participants (mean age, 63 years; range, 36-89 years; 13 women; 2019-2021) with meningiomas. Region- and voxel-specific Ki were determined using Patlak analysis with a validated population-based reference tissue TAC model built from an independent data set of nine participants. Mean and maximum absolute and relative-to-superior-sagittal-sinus SUVs were extracted from the entire 50 minutes (SUV50) and last 10 minutes (SUV10) of acquisition. SUV versus Ki Spearman correlation, SUV and Ki meningioma versus posttreatment-change Mann-Whitney U tests, and SUV50 versus SUV10 Wilcoxon matched-pairs signed rank tests were performed. Results Absolute and relative maximum SUV50 demonstrated a strong positive correlation with Patlak Ki in meningioma (r = 0.82, P < .001 and r = 0.85, P < .001, respectively) and posttreatment-change lesions (r = 0.88, P = .007 and r = 0.83, P = .02, respectively). Patlak Ki images yielded higher lesion contrast by mitigating nonspecific background signal. All SUV50 and SUV10 metrics differed between meningioma and posttreatment-change regions (P < .001). Within the meningioma group, SUV10 attained higher mean scores than SUV50 (P < .001). Conclusion Combined SUV and Patlak Ki68Ga-DOTATATE PET/MRI enabled multiparametric evaluation of meningioma, offering the potential to enhance lesion contrast with Ki imaging and optimize the SUV measurement postinjection window. Keywords: Molecular Imaging-Clinical Translation, Neuro-Oncology, PET/MRI, Dynamic, Patlak ClinicalTrials.gov registration no. NCT04081701 © RSNA, 2022.

Stereotactic radiosurgery for vestibular schwannomas in neurofibromatosis type 2 patients: a systematic review and meta-analysis.

INTRODUCTION: Neurofibromatosis type 2 (NF2) is characterized by often bilateral vestibular schwannomas (VS) that result in progressive hearing loss and compression of nearby brainstem structures causing cranial nerve palsies. Treatment of these tumors remains challenging, as both surgical removal and expectant management can result in symptom progression. Stereotactic radiosurgery (SRS) has been investigated for the management of NF2-associated VS; however, the role, promises, and pitfalls of this treatment modality remain unclear. METHODS: Ovid MEDLINE, EMBASE, Web of Science, and Cochrane Reviews were searched for studies assessing SRS outcome in NF2-associated VS only. Primary endpoints included tumor control, serviceable hearing, presence of tinnitus, and cranial nerve V and VII symptoms. RESULTS: A total of 16 studies (589 patients harboring 750 tumors) were analyzed. Clinical tumor control was achieved in 88% of cases (95% CI 80-95%); salvage surgery was needed in 8% (95% CI 4-13%) of cases. Treatment resulted in a worsening of pre-treatment serviceable hearing (OR = 0.26, p < 0.01), increased facial nerve (OR = 1.62, p < 0.01) and trigeminal nerve (OR = 1.42, p = 0.07) impairment. The incidence of vestibular symptoms and hydrocephalus were not consistently reported and thus could not be assessed. CONCLUSIONS: The treatment of NF2-associated VS continues to pose a challenge, as current SRS regimens result in impaired hearing and worse cranial nerve comorbidities, despite achieving high tumor control. It remains unclear if these findings have to be regarded as treatment complications or, rather, continued disease progression.

Assessing the long-term safety and efficacy of gamma knife and linear accelerator radiosurgery for vestibular schwannoma: A systematic review and meta-analysis.

BACKGROUND: Differences in long-term outcomes of single-fraction stereotactic radiosurgery (SRS) between gamma knife (GK) and linear accelerator (LINAC) systems for vestibular schwannoma (VS) management remain unclear. To investigate differences in safety and efficacy between modalities, we conducted a meta-analysis of studies over the past decade. METHODS: MEDLINE, EMBASE, and Cochrane databases were queried for studies with the following inclusion criteria: English language, published between January 2010 and April 2020, cohort size ≥30, and mean/median follow-up ≥5 years. Odds ratios (OR) compared rates of tumor control, hearing preservation, and cranial nerve toxicities before and after SRS. RESULTS: Thirty-nine studies were included (29 GK, 10 LINAC) with 6516 total patients. Tumor control rates were 93% (95% CI 91-94%) and 94% (95% CI 91-97%) for GK and LINAC, respectively. Both GK (OR 0.06, 95% CI 0.02-0.13) and LINAC (OR 0.47, 95% CI 0.29-0.76) reduced odds of serviceable hearing. Neither GK (OR 0.71, 95% CI 0.41-1.22) nor LINAC (OR 1.13, 95% CI 0.64-2.00) impacted facial nerve function. GK decreased odds of trigeminal nerve (TN) impairment (OR 0.55, 95% CI 0.32-0.94) while LINAC did not impact TN function (OR 1.45, 95% CI 0.81-2.61). Lastly, LINAC offered decreased odds of tinnitus (OR 0.15, 95% CI 0.03-0.87) not observed with GK (OR 0.70, 95% CI 0.48-1.01). CONCLUSIONS: VS tumor control and hearing preservation rates are comparable between GK and LINAC SRS. GK may better preserve TN function, while LINAC decreases tinnitus rates. Future studies are warranted to investigate the efficacy of GK and LINAC SRS more directly.

Outcomes following upfront radiation versus monitoring in atypical meningiomas: 16-year experience at a tertiary medical center.

BACKGROUND: The role of postoperative upfront radiotherapy (RT) in the management of gross totally resected atypical meningiomas remains unclear. This single-center retrospective review of newly diagnosed histologically confirmed cases of World Health Organization (WHO) Grade II atypical meningioma at Weill Cornell Medicine from 2004 to 2020 aims to compare overall survival (OS) and progression-free survival (PFS) of postoperative upfront RT versus observation, stratified by resection status (gross total resection [GTR] vs subtotal resection [STR]). METHODS: Ninety cases of atypical meningioma were reviewed (56% women; median age 61 years; median follow-up 41 months). RESULTS: In patients with GTR, hazard ratio (HR) of PFS was 0.09 for postoperative upfront RT versus observation alone (95% confidence interval [CI] 0.01-0.68; P = .02), though HR for OS was not significant (HR 0.46; 95% CI 0.05-4.45; P = .5). With RT, PFS was 100% at 12 and 36 months (compared to 84% and 63%, respectively, with observation); OS at 36 months (OS36) was 100% (compared to 94% with observation). In patients with STR, though PFS at 36 months was higher for RT arm versus observation (84% vs 74%), OS36 was 100% in both arms. HR was not significant (HR 0.76; 95% CI 0.16-3.5; P = .73). CONCLUSIONS: This retrospective study suggests postoperative upfront RT following GTR of atypical meningioma is associated with improved PFS compared to observation. Further studies are required to draw conclusions about OS.

Efficacy and comorbidities of hypofractionated and single-dose radiosurgery for vestibular schwannomas: a systematic review and meta-analysis.

BACKGROUND: Vestibular schwannomas (VS) are tumors of the cerebellopontine angle with significant morbidity, causing hearing loss, tinnitus, and trigeminal and facial nerve compromise. An effective alternative to microsurgical resection is stereotactic radiosurgery (SRS), which can be delivered in either single-fraction (SRS) or hypofractionated stereotactic radiotherapy (hSRT) (3-5 treatments) regimens. It remains unclear which fractionation regimen provides superior outcomes. METHODS: Ovid MEDLINE, EMBASE, CINAHL, and Cochrane Reviews were searched for studies either comparing hSRT with SRS or focusing on hSRT alone in treating VS. Primary endpoints included tumor control, serviceable hearing, tinnitus, and cranial nerve V and VII symptoms. A random-effects analysis was employed to compare pre- and post-treatment effects (hSRT alone) or SRS and hSRT outcomes (two-arm studies). RESULTS: This analysis included 21 studies focusing on hSRT alone and 13 studies comparing SRS and hSRT. Significant heterogeneity was observed. Overall, when hSRT was analyzed alone, crude tumor control was achieved in 94% (95% CI: 88%, 99%) of 1571 patients. There was no difference between pre- and post-treatment odds ratios (OR) of tinnitus, facial, or trigeminal impairment. Serviceable hearing was diminished following hSRT (OR = 0.60, 95% CI: 0.44, 0.83). Comparison with SRS showed no difference with respect to tumor control, serviceable hearing, trigeminal or facial nerve impairment. CONCLUSIONS: hSRT achieved excellent tumor control and, with the exception of serviceable hearing, did not result in worse post-treatment cranial nerve symptomatology. Analysis of comparative studies between hSRT and SRS did not reveal any significant difference in either tumor control or treatment morbidities.

Outcomes of stereotactic radiosurgery for large vestibular schwannomas: a systematic review and meta-analysis.

BACKGROUND: Large vestibular schwannomas (VS) pose a treatment challenge for both microsurgery (MS) and stereotactic radiosurgery (SRS). Technical developments have allowed for safer irradiation of large tumors. It remains unclear if SRS can achieve appropriate tumor control and acceptable cranial nerve toxicities. In this study, we assess outcomes of irradiation for large VS. METHODS: PubMed MEDLINE, EMBASE, Web of Science, and Cochrane were searched for all the studies assessing SRS outcome in large VS. Primary endpoints included clinical and radiographic tumor control, need for salvage surgery, serviceable hearing, cranial nerve V and VII impairment, presence of hydrocephalus requiring shunting, and presence of vertigo/dizziness. RESULTS: Twenty-two studies were identified that met selection criteria for analysis from an initial pool of 1272 reports. They were evaluated according to treatment protocol: 1) single-dose SRS (13 studies, 483 patients), 2) combination of MS and SRS (7 studies, 182 patients), and 3) fractionated SRS (3 studies, 82 patients). Tumor control was achieved in 89%, 94%, and 91% of patients, respectively. Odds ratios (ORs) of post- over pretreatment serviceable hearing were 0.42 (P < .01), 0.47 (P = .05), and 0.60 (P = .22); for facial nerve impairment, these ORs were 1.08 (P = .69), 3.45 (P = .28), and 0.87 (P = .71), respectively. CONCLUSIONS: The management of large VS remains challenging. All treatment modalities resulted in high tumor control rates and worsening of pretreatment hearing. None, however, caused significant facial nerve impairment, suggesting that management strategies incorporating focal irradiation can be successful.

Time to administration of stereotactic radiosurgery to the cavity after surgery for brain metastases: a real-world analysis.

OBJECTIVE: Publications on adjuvant stereotactic radiosurgery (SRS) are largely limited to patients completing SRS within a specified time frame. The authors assessed real-world local recurrence (LR) for all brain metastasis (BM) patients referred for SRS and identified predictors of SRS timing. METHODS: The authors retrospectively identified BM patients undergoing resection and referred for SRS between 2012 and 2018. Patients were categorized by time to SRS, as follows: 1) ≤ 4 weeks, 2) > 4-8 weeks, 3) > 8 weeks, and 4) never completed. The relationships between timing of SRS and LR, LR-free survival (LRFS), and survival were investigated, as well as predictors of and reasons for specific SRS timing. RESULTS: In a cohort of 159 patients, the median age at resection was 64.0 years, 56.5% of patients were female, and 57.2% were in recursive partitioning analysis (RPA) class II. The median preoperative tumor diameter was 2.9 cm, and gross-total resection was achieved in 83.0% of patients. All patients were referred for SRS, but 20 (12.6%) did not receive it. The LR rate was 22.6%, and the time to SRS was correlated with the LR rate: 2.3% for patients receiving SRS at ≤ 4 weeks postoperatively, 14.5% for SRS at > 4-8 weeks (p = 0.03), and 48.5% for SRS at > 8 weeks (p < 0.001). No LR difference was seen between patients whose SRS was delayed by > 8 weeks and those who never completed SRS (48.5% vs 50.0%; p = 0.91). A similar relationship emerged between time to SRS and LRFS (p < 0.01). Non-small cell lung cancer pathology (p = 0.04), earlier year of treatment (p < 0.01), and interval from brain MRI to SRS (p < 0.01) were associated with longer intervals to SRS. The rates of receipt of systemic therapy also differed significantly between patients by category of time to SRS (p = 0.02). The most common reasons for intervals of > 4-8 weeks were logistic, whereas longer delays or no SRS were caused by management of systemic disease or comorbidities. CONCLUSIONS: Available data on LR rates after adjuvant SRS are often obtained from carefully preselected patients receiving timely treatment, whereas significantly less information is available on the efficacy of adjuvant SRS in patients treated under "real-world" conditions. Management of these patients may merit reconsideration, particularly when SRS is not delivered within ≤ 4 weeks of resection. The results of this study indicate that a substantial number of patients referred for SRS either never receive it or are treated > 8 weeks postoperatively, at which time the SRS-treated patients have an LR risk equivalent to that of patients who never received SRS. Increased attention to the reasons for prolonged intervals from surgery to SRS and strategies for reducing them is needed to optimize treatment. For patients likely to experience delays, other radiotherapy techniques may be considered.

[68Ga]-DOTATATE PET/MRI as an adjunct imaging modality for radiation treatment planning of meningiomas.

BACKGROUND: Meningiomas express high levels of somatostatin receptor 2 (SSTR2). SSTR2-targeted PET imaging with [68Ga]-DOTATATE can aid with distinguishing residual meningioma from reactive changes in the postoperative setting. We present initial dosimetric analyses, acute events, and local control data utilizing [68Ga]-DOTATATE PET/MRI-assisted target delineation for prospectively-treated intermediate-risk meningiomas. METHODS: Twenty-nine patients underwent DOTATATE PET/MRI meningioma evaluation in 2019. Eight patients with 9 postoperative meningiomas met RTOG 0539 intermediate-risk criteria (recurrent WHO grade I, 1/9; WHO grade II, 8/9). Target volumes were created using DOTATATE PET/MRI to determine residual disease and received a nominal dose of 35.0 Gy over 5 fractions. For comparison, cases were recontoured and planned with MRI alone per RTOG 0539 guidelines. Mean and maximum equivalent 2 Gy doses were generated for target volumes and organs at risk (OAR) within 1 cm of the PTV and compared using Wilcoxon matched pairs signed rank test. RESULTS: DOTATATE PET/MRI-guided planning significantly reduced mean PTV (11.12 cm3 compared to 71.39 cm3 based on MRI alone, P < .05) and mean and max dose to the whole brain, optic nerves, and scalp. PET/MRI plans resulted in at least 50% reduction of mean and max doses to the lens, eyes, chiasm, cochlea, brainstem, and hippocampi. One patient experienced focal alopecia. There were no local recurrences at 6 months. CONCLUSION: Incorporating DOTATATE-PET/MRI for postoperative target delineation in patients with intermediate-risk intracranial meningiomas results in PTV reduction and decreased OAR dose. Our findings warrant larger studies evaluating DOTATATE-PET/MRI in the radiotherapeutic planning of postoperative meningiomas.